A relatively clear picture emerges, relating chemotherapy-induced cognitive decline to neurogenesis and neurogenesis to learning. However, despite some recent advances (Lacefield

et al., 2012), it is not known how disruption of neurogenesis alters learning-related synchronised neural activity such as theta oscillations in the hippocampus (3–12 Hz, see Buzsáki, 2002). Proportionately more hippocampal theta activity predicts faster and better learning (Berry Transmembrane Transporters activator & Thompson, 1978; Nokia et al., 2009, 2012), and learning itself induces theta activity during training in animals (Hoffmann & Berry, 2009; Wikgren et al., 2010) and humans (for reviews see Duzel et al., 2010; Jutras & Buffalo, 2010). It is suggested that synchronised oscillatory activity facilitates communication between anatomically distant, but functionally related, structures during learning. Thus, a disruption in theta activity in response to chemotherapy may prevent interregional communication, leading to deficits in learning. The hippocampus is necessary for many aspects of learning, but typically not for long-term memory storage (Takehara et al., 2003). Therefore, we hypothesised

that chemotherapy would disrupt learning but not memory. To test these hypotheses, adult male Sprague–Dawley rats were treated with temozolomide (TMZ) and then trained on classical eyeblink conditioning, while hippocampal local-field potentials were recorded. Dividing cells were labeled at different time points to allow examination of the various potential effects of TMZ on adult neurogenesis. TMZ is a chemotherapeutic agent selleck used in a cyclic manner for several months to treat central nervous system tumors (gliomas) in both children and adults (Lashkari et al., 2011). Trace and very long delay (VLD) conditioning both require an intact hippocampus for learning (Beylin et al., 2001), whereas standard delay conditioning does not (Schmaltz & Theios, 1972). Also, in a previous study by Shors

et al. (2001), antimitotic treatment had no effect on delay conditioning, whereas it severely impaired trace conditioning. Therefore, it was hypothesised that only trace and VLD conditioning would be impaired after chemotherapy. As chemotherapy Chloroambucil is assumed to exert its negative effects on cognition by disrupting neurogenesis, and the memory for a previously acquired trace-conditioned response is independent of the hippocampus (Takehara et al., 2003), i.e. is stored by mature neurons, it was also hypothesised that chemotherapy would leave the retrieval of trace memories intact. A total of 53 self-bred (Department of Psychology, Rutgers University) adult male Sprague–Dawley rats were used as subjects. They were 60–75 days old and weighed, on average, 366 g (standard error of the mean, ± 4 g) at the beginning of the experiment. Each rat was weighed weekly (Fig. S1). All rats were single-housed during the experiment, and food and water were available ad libitum.